New developments in myeloid cell research have dramatically changed our understanding of macrophage ontogeny and function. Our decades-long understanding of the origin of macrophages has been overturned, as we now recognize that some tissue macrophages are not derived from continuously infiltrating monocytes that mature to macrophages, but rather exist as self-replicating cells derived from yolk sac progenitors during fetal development. In addition, within each one of these ontogenically distinct populations, there exist specific functional phenotypes that are polarized in response to signaling molecules in the extracellular milieu. We have novel data showing that peritoneal macrophages and microglia harbor transcriptional competent SIV genomes in infected macaques that have been virally suppressed by combination antiretroviral therapy (cART) for more than 500 days p.i. These findings suggest that some specialized macrophages represent a different type of viral reservoir with unique traits. Latency studies, however, have focused on resting CD4+ T cells, and little is known about the mechanisms that modulate latency and reactivation in other cell types also susceptible to HIV infection. Therefore, we propose to: 1) Characterize tissue macrophages in the context of ontogeny and polarization in uninfected, SIV-infected, and SIV-infected cART-treated macaques; 2) Develop in vitro models in primary tissue macrophages and monocyte-derived macrophages for the characterization of mechanisms associated with viral latency and reactivation.